S247: ADDING RUXOLITINIB AND DECITABINE TO BU/CY CONDITIONING REGIMENS TO PROPHYLAXIS POST-TRANSPLANT RELAPSE IN HIGH-RISK AML IS SAFE AND EFFECTIVE: A PROSPECTIVE, PHASE II STUDY
Authors: Yujun Wei, Kun Qian, Lili Wang, Fei LI, Nan Wang, Bo Peng, Yanan Wen, Lu Wang, Lingmin Xu, Xiangshu Jin, Liping Dou, Dai-Hong Liu
Journal: HemaSphere (2023)

Background: Patients with high-risk acute myeloid leukemia (AML) always have poor outcome. Even after allogeneic stem cell transplantation (allo-HSCT), up to 40%-60% of high-risk AML patients still relapse. Intensification of the conditioning regimen has been investigated for decades aiming to reduce relapse of the high-risk hematologic malignancies after allo-HSCT. Up to now, most intensified conditioning regimens reduced relapse accompanied by increase of non-relapse mortality. Decitabine is a hypomethylating agent that has shown efficacy in high-risk AML and relapse/refactary AML for around 20% reduction in relapse rates. In vitro and in vivo studies revealed that proliferation of AML cells was inhibited by ruxolitinib by inhibition of JAK–STAT signaling and restoration of hematopoietic differentiation with anti-leukemic therapy. Rampal et al. use the leukemic mouse model found that combination of decitabine and ruxolitinib resulted in increased anti-leukemic efficacy in suppressing proliferation of AML cells. Data from a phase II study on efficacy of ruxolitinib and decitabine for patients with myeloproliferative neoplasm in accelerated and blast phase patients demonstrated the combination was well tolerated, and the median OS was 9.5 months. Considering the adverse effects of ruxolitinib and decitabine were limited and not overlapping, we supposed the combination would be tolerable. Aims: The purpose of this study is to investigate the efficacy and safety of ruxolitinib and decitabine followed by Bu/Cy conditioning for high-risk AML adult patients who received allo-HSCT. Methods: Thirty-seven AML patients were enrolled from September 2020 to March 2022. High-risk AML patients met the following inclusion criteria: (1) Relapsed/refractory; (2) poor genetic abnormalities based on the ELN2017 classification; (3) not achieved complete remission after the first cycle of induction chemotherapy; (4) MRD (+) prior to transplantation. All patients provided written informed consent. The exclusion criteria were (1) pregnant female; (2) patients with mental disorders or other states unable to comply with the protocol; (3) AML with t (15;17). Ruxolitinib (35mg bid, day -15 to -10, tapered and discontinued on day -1) and decitabine (20 mg/m2/day, day -15 to -10) were administered prior to start of Bu/Cy conditioning. Results: The median age was 47 (10-62) years. Twenty-four patients were at CR (CR1, 17; ≥CR2, 7) and 13 (35.1%) patients were at non-remission status (NR) prior to conditioning. Thirteen of the 17 CR1 patients had poor risk cytogenetics. The other 4 patients with favorable or intermediate cytogenetics did not achieve complete remission after the first cycle of chemotherapy. The mutation results of the patients’ second-generation sequencing are shown in Figure 1. Twelve (50%) of the CR patients were MRD+positive prior to conditioning. The white blood cell counts in six(16.2%) patients were ≥100 ×109/L. With a median follow-up of 578 (266-896) days. The 2-year cumulative incidence of relapse was 34.3%, and that of non-relapse mortality (NRM) was 13.2%. That of acute GVHD grade II-IV at 100 days was 35.0%, and that of acute GVHD grade III- IV was 10.5%. The cumulative incidence of chronic GVHD at 2 years was 10.9%, and that of moderate and severe chronic GVHD was 5.4%. The 2-year probabilities of OS, DFS, and GRFS were 55.1%, 52.6%, and 50.7%. Summary/Conclusion: In patients with high-risk AML, adding ruxolitinib and decitabine to Bu/Cy conditioning was tolerable and effective for reducing relapse. (ClinicalTrials.govnumber, NCT04582604).Keywords: AML, Acute graft-versus-host disease, Conditioning, Hematopoietic cell transplantation